Spatial learning and hippocampal volume in male deer mice: relations to age, testosterone and adrenal gland weight

Endoscopic carpal tunnel release is a controversial procedure used in the treatment of carpal tunnel syndrome. Although endoscopic carpal tunnel release is associated with less incisional pain and faster recovery time than the open carpal tunnel release, opponents of endoscopic carpal tunnel release suggest that its benefits are outweighed by its higher complication rates from median nerve transection and transient numbness of the fingers. Because of the huge economic and social impact of carpal tunnel syndrome in this country, we performed a cost-effectiveness analysis comparing endoscopic carpal tunnel release and open carpal tunnel release using guidelines established by the Panel on Cost-Effectiveness in Health and Medicine of the U.S. Public Health Service. A decision analytic model was used to measure differences in cost and effectiveness--expressed as quality-adjusted life-years (QALYs)--between endoscopic carpal tunnel release and open carpal tunnel release. The societal perspective was chosen, and probabilities for various outcomes for the two procedures were obtained from published randomized-controlled trials. Cost data were derived from the Medicare Resource-Based Relative Value Units published in the Federal Register. QALYs were obtained from two groups of health care providers using a utility-assessment questionnaire. Using probabilities for various outcomes from the two published randomized-controlled trials comparing endoscopic carpal tunnel release and open carpal tunnel release, we constructed a decision tree to derive both the cost and the QALYs for the two procedures. The incremental cost difference between endoscopic carpal tunnel release and open carpal tunnel release was $46, using Medicare cost and probabilities of various outcomes derived from a study by Brown et al. in 1993. We calculated QALYs for five age groups--25, 35, 45, 55, 65--assuming a life expectancy of 75 years. The marginal effectiveness (QALY of endoscopic carpal tunnel release minus QALY of open carpal tunnel release) ranged from 0.235 QALY for the 25-year-old age group to 0.066 QALY for the 65-year-old age group, giving a cost-effectiveness ratio of $195/QALY and $693/QALY, respectively. When compared with other accepted medical interventions such as breast cancer screening ($4836/QALY) and exercise to prevent coronary heart disease ($13,508/QALY), endoscopic carpal tunnel release seems to be cost-effective. However, our sensitivity analysis indicated that the cost-effectiveness ratio was very sensitive to a major complication such as median nerve injury. For endoscopic carpal tunnel release to be a cost-effective procedure, the incidence of median nerve injury must be one percentage point less for endoscopic carpal tunnel release than for open carpal tunnel release. Based on the data from the randomized-controlled trials, endoscopic carpal tunnel release seems to be a cost-effective procedure; however, before it can be recommended, greater emphasis must be given to the training of surgeons in this new technique, so that major complications such as median nerve injuries can be avoided. In addition, future studies must better define the actual incidence of nerve injuries for both endoscopic carpal tunnel release and open carpal tunnel release in the community setting.     

Loss of atm radiosensitizes multiple p53 null tissues

An unusual clinical finding in ataxia-telangiectasia, a human disorder caused by mutations in atm, is exquisite sensitivity to gamma irradiation. By contrast, homozygous deletion of p53 is marked by radiation resistance in certain tissue compartments. Previous studies (A. J. Levine, Cell, 88: 323-331, 1997) have shown that, in vitro, p53-deficient bone marrow cells are resistant to gamma irradiation. Furthermore, the gastrointestinal radiosensitization engendered by the loss of atm has recently been shown (C. H. Westphal et al., Nat. Genet., 16: 397-401, 1997) to be independent of p53. Expanding on previous work, we have looked at in vivo bone marrow resistance in p53-deficient mice. Our results indicate that inbred FVB strain p53 null mice survive lethal irradiation doses because of bone marrow resistance. Moreover, the deletion of atm radiosensitizes even p53 null bone marrow and mouse embryonic fibroblast cells. The results presented here argue that the loss of atm radiosensitizes multiple tissues in a p53-independent manner. Hence, functional inhibition of atm in p53 null and p53 wild-type human tumors may be a useful adjunct to gamma irradiation-based antitumor therapy.     

Imaging and quantitation of dopamine transporters with iodine-123-IPT in normal and Parkinson's disease subjects

Iodine-123-N-(3-iodopropene-2-yl)-2beta-carbomethoxy-3beta-( 4-chlorophenyl) tropane (123I-IPT) is a new dopamine transporter ligand that selectively binds the dopamine reuptake sites. Transporter concentrations have been known to decrease in Parkinson's disease patients. The purpose of this study was to evaluate the usefulness of IPT as an imaging agent for measuring changes in transporter concentrations in Parkinson's disease. METHODS: IPT labeled with 6.78 +/- 0.67 mCi 123I was injected intravenously as a bolus into eight normal controls (mean age 41 +/- 12 yr) and 17 Parkinson's disease patients (mean age 55 +/- 9 yr). Dynamic SPECT scans of the brain were then performed for 5 min each over 120 min on a triple-headed gamma camera equipped with medium-energy collimators. Regions of interest were drawn on the middle set of the image at the level of the basal ganglia (BG) for each subject. Time-activity curves were generated for the left BG, right BG and occipital cortex (OCC). The empirical ratios between BG-OCC and OCC, which represent specific-to-nonspecific binding ratios, were computed at various time points. The statistical parameter k3/k4 was estimated by two methods: a variation of the graphic method that derives the ratio of ligand distribution volumes (R[V]) and the area ratio method (R[A]), in which the ratio is calculated from the areas under the specific and nonspecific binding activity curves. RESULTS: The mean (BG-OCC)/OCC ratio for normal controls (3.07 +/- 0.73) was significantly higher than that for Parkinson's disease patients at 115 min (1.10 +/- 0.56) (p = 2.76 x 10[-5]). The mean R(V) and R(A) for normal controls were 2.06 +/- 0.27 and 1.50 +/- 0.15, respectively. The mean R(V) and R(A) for Parkinson's disease patients were 0.78 +/- 0.31 and 0.65 +/- 0.24, respectively. Both R(V) and R(A) for normal controls were significantly higher than those for Parkinson's disease patients (p values for R(V) and R(A) were 1.91 x 10(-8) and 3.46 x 10(-10), respectively). The R(V) has linear relationships with both R(A) and (BG-OCC)/OCC ratio at 115 min. The R(V) has a higher correlation (r = 0.99) with R(A) than it does with (BG-OCC)/OCC (r = 0.93). CONCLUSION: The R(V), R(A) and (BG-OCC)/OCC for Parkinson's disease patients were clearly separated from those of normal controls, and they may be useful outcome measures for clinical diagnosis. The simplest (BG-OCC)/OCC ratio, requiring a single late time point, could be useful in clinical situations, whereas R(V) or R(A) is preferred when the dynamic data are available. The findings suggest that 123I-IPT is a useful tracer for diagnosing Parkinson's disease and studying dopamine reuptake sites.     

Elevated transforming growth factor-alpha levels in bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome

The acute respiratory distress syndrome (ARDS) frequently results in a fibroproliferative response that precludes effective alveolar repair. Transforming growth factor-alpha (TGF-alpha), a potent epithelial and mesenchymal cell mitogen, may modulate the response to lung injury. In this study, we determined whether bronchoalveolar lavage fluid (BALF) concentrations of TGF-alpha are increased during the first 2 wk after the onset of ARDS and, if so, whether increased TGF-alpha levels in lavage fluid are associated with increased levels of procollagen peptide III (PCP III), a biological marker of fibroproliferation, and with increased fatality rates. We enrolled 74 consecutive patients with ARDS prospectively identified on admission to the intensive care unit of a tertiary care hospital, and 11 patients with chronic interstitial lung disease. Thirteen healthy volunteers served as control subjects. TGF-alpha concentrations were measured in BALF recovered on Days 3, 7, and 14 after the onset of ARDS (total of 130 lavage samples). TGF-alpha was detected in the lavage fluid of 90% of patients with ARDS (67 of 74), and in 100% of patients with idiopathic pulmonary fibrosis (IPF) (10 of 10), but in none of 13 normal volunteers. At each day tested, the median lavage TGF-alpha level of patients with ARDS was significantly higher than that of normals. The overall fatality rate was 45% (33 of 74 patients). In a univariate analysis, the median TGF-alpha levels in nonsurvivors were 1.5-fold higher at Day 7 (p = 0.06) and 1.8-fold higher at Day 14 (p = 0.048). The fatality rate was 4 times higher (CI 1.6, 17.5) for patients with both increased lavage TGF-alpha and PCP III concentrations at Day 7 than for patients with low TGF-alpha and PCP III values, indicating a synergistic relationship between TGF-alpha and PCP III. We conclude that increased levels of TGF-alpha in BALF are common in patients with ARDS and that lavage TGF-alpha is associated with a marker of the fibroproliferative response in sustained ARDS.     

Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype correlations

Spinocerebellar ataxia type 6 (SCA6) is the most recently identified mutation causing autosomal-dominant cerebellar ataxia without retinal degeneration (ADCA). The SCA6 mutation is allelic with episodic ataxia type 2 (EA-2), but the two differ clinically because of the presence of progressive, rather than episodic, ataxia in SCA6. SCA6 accounts for 12% of families with ADCA in an ethnically heterogeneous population of patients. Clinical examination, quantitative eye movement testing, and imaging data show that the brainstem is normal in most patients with SCA6, especially within the first 10 years of symptoms. Most patients show progressive ataxia from the onset, but several patients show an episodic course resembling EA-2. Thus, SCA6 mutations not only account for patients with ADCA I and ADCA III phenotypes but also for some patients presenting with episodic features that are typical for EA-2. Interestingly, a compound heterozygote for the SCA6 expansion manifested an earlier onset and more rapid course than family members with the same larger expanded allele.     

Therapeutic levels of human protein C in rats after retroviral vector-mediated hepatic gene therapy

Protein C deficiency results in a thrombotic disorder that might be treated by expressing a normal human protein C (hPC) gene in patients. An amphotropic retroviral vector with a liver-specific promoter and the hPC cDNA was delivered to rat hepatocytes in vivo during liver regeneration. Expression of hPC varied from 55 to 203 ng/ml (1.3-5.0% of normal) for 2 wk after transduction. Expression increased to an average of 900 ng/ml (22% of normal) in some rats and was maintained at stable levels for 1 yr. All of these rats developed anti-hPC antibodies and exhibited a prolonged hPC half-life in vivo. The hPC was functional as determined by a chromogenic substrate assay after immunoprecipitation. We conclude that most rats achieved hPC levels that would prevent purpura fulminans, and that hepatic gene therapy might become a viable treatment for patients with severe homozygous hPC deficiency. Anti-hPC antibodies increased the hPC half-life and plasma levels in some rats, but did not interfere with its functional activity. Thus, the development of antibodies against a plasma protein does not necessarily abrogate its biological effect in gene therapy experiments.